Abstract: Engineering Effective Revascularization Technologies for Ischemia in Disease States Chronic myocardial ischemia disease affects more than 27 milion patients in the United States and is the leading cause of morbidity and mortality in developed countries. Peripheral ischemic is even more prevalent being present in 12-20% of the population aged 65 and older in the US. Ischemic disease most often occurs as a result of arterial narrowing due to long-standing atherosclerotic disease processes. This arterial remodeling leads to a reduction in blood flow and, ultimately, causes organ dysfunction and failure. Current therapies for treating ischemia include the use of percutaneous interventions to physically open the artery or surgical methods to reroute blood flow to the poorly perfused tissue. These methods have significant limitations and eventually fail in the long-term. The most effective means to treat ischemic disease would be to revascularize the tissue by stimulating the development of native vasculature. Many studies have been done to attempt to use growth factors, growth factor genes and implanted cells to facilitate revascularization of ischemic tissues. While these treatments have been effective in experimental models, clinical trials have shown them to have limited efficacy in treating human disease. This proposal aims to understand why growth factor based therapies have failed to treat ischemia in patients and seeks to create novel therapeutics to increase growth factor effectiveness in this context. Our fundamental hypothesis is that the reason these therapies have failed is that tissues with long standing disease and exhausted compensatory mechanisms are unable to respond with appropriate growth factor signaling. Through basic studies on diseased cells and tissues, we will perform a detailed analysis of signaling pathways to identify the reasons for the ineffective growth factor signaling. We recently developed novel techniques allowing the replacement of missing receptors and co-receptors on the cell surface. Using these and other innovative methods we will pursue novel therapeutic drug formulations that can be utilized as co-treatments to allow growth factors to be efficacious in the presence of clinical disease. We will test these new treatments in clinically relevant animal models of peripheral and myocardial ischemia. Together, the studies performed and the tools developed will increase our understanding of how tissues become resistant to revascularization therapies and may lead to more effective treatments for this widespread and debilitating disease. Public Health Relevance: Chronic myocardial ischemia disease affects about 27 million patients in the United States and is the leading cause of morbidity and mortality in developed countries. Peripheral ischemic is even more prevalent being present in 12-20% of the population aged 65 and older in the US. This proposal seeks to understand why growth factor based therapies have failed to treat ischemia in patients and seeks to create novel therapeutics to increase growth factor effectiveness in this context.